A steady accumulation of data argues that prion-like mechanisms feature in the pathogenesis of most or all age-dependent neurodegenerative diseases. For both the mammalian and fungal prions, we have succeeded in producing a variety of synthetic strains. The physical characteristics of the synthetic prion strains breed true upon passage and are predictive of infectivity: there is a clear relationship between the length of the incubation time and the structural stability for the mammalian prion strains. The ability to create different infectious conformations and introduce them into yeast makes the [PSI+] system uniquely well suited for studying how changes in the conformation of proteins determine their physiological impact. While elucidating the molecular mechanisms that specify the properties of prion strains is likely to create improved models for experimental AD, it will probably be insufficient in the quest for effective therapeutics. That being the case, we plan to study cultured neurons produced from fibroblasts using stem cell technology. A systematic screen of TFs identified a pool of 3 TFs that can induce mouse fibroblasts to differentiate into neurons. We plan to produce neurons from human fibroblasts obtained from carriers with APP or PrP gene mutations that cause familial AD or CJD, respectively. These neurons will be used in studies on the propagation of PrP and A? amyloids in cells and transgenic mice. Deciphering the language of prion strains will open many new avenues of investigation that are likely to reach far beyond the pathogenesis of neurodegeneration. We do not understand the rules of protein-based inheritance and have little appreciation of how prions function in the normal physiology of the cell as well as cause neurodegeneration.